Browsing by Author "Mahasa, Khaphetsi Joseph"

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    Mathematical Modelling of Tumour-Immune Interactions and Cancer Therapy
    (Stellenbosch : Stellenbosch University, 2017-12) Mahasa, Khaphetsi Joseph; Ouifki, Rachid; Eladdadi, Amina; Stellenbosch University. Faculty of Science. Dept. of Mathematical Sciences. Division Mathematics.
    ENGLISH ABSTRACT : The immune system plays a key role against the development and progression of tumor cells mainly because of its capability of recognizing and destroying cancerous cells. While incredible research efforts have been made over the past decades to decipher the complexity of the tumor-immnue interactions, there is still a lack of a definite and complete picture of these interactions. This may be attributed to the fact that tumor cells develop intricate mechanisms to evade detection and control by the immune system and resist treatments. Although this has been attributed to tumor escape from the immune system, no quantitative studies have been made to precisely characterize key tumor evasion mechanisms from immune surveillance. There is a growing need for new modeling approaches that take into account the complexity of immune system response and/or tumor escape mechanisms, and the recent advances in cancer therapy. This lack has motivated the work in this thesis. We focused our research on addressing the following three scientific questions: (1) How do tumors evolve by escaping immune surveillance? (2) How can oncolytic virus infection of some normal cells in the vicinity of tumor cells enhance oncolytic virotherapy? (3) How can the use of cell carriers for the delivery of oncolytic virus particles to tumor sites affect the outcomes of oncolytic virotherapy in the presence of active immune response? To address these major questions, we have devised three novel mathematical models to study the behaviour of tumor cells following their interactions with key cytotoxic immune cells and oncolytic viruses. The results herein this thesis show the development of immunoresistant phenotype by tumor cells to effectively evade the immune system. This thesis supports the natural killer (NK) cell-based immunotherapeutic approaches that are aimed at enhancing the immune surveillance of tumors. Our work also highlights an interesting possibility of infecting some normal cells in the vicinity of tumor cells to increase the oncolytic infectious titers within tumor microenvironment. Additionally, our findings provide pertinent information on how the use of certain cell carriers may enhance oncolytic virotherapy in the presence of effective immune response within the tumor microenvironment.
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    Mesenchymal stem cells used as carrier cells of oncolytic adenovirus results in enhanced oncolytic virotherapy
    (Springer Nature, 2020-01-16) Mahasa, Khaphetsi Joseph; De Pillis, Lisette; Ouifki, Rachid; Eladdadi, Amina; Maini, Philip; Yoon, A-Rum; Yun, Chae-Ok
    Mesenchymal stem cells (MSCs) loaded with oncolytic viruses are presently being investigated as a new modality of advanced/metastatic tumors treatment and enhancement of virotherapy. MSCs can, however, either promote or suppress tumor growth. To address the critical question of how MSCs loaded with oncolytic viruses affect virotherapy outcomes and tumor growth patterns in a tumor microenvironment, we developed and analyzed an integrated mathematical-experimental model. We used the model to describe both the growth dynamics in our experiments of firefly luciferase-expressing Hep3B tumor xenografts and the effects of the immune response during the MSCs-based virotherapy. We further employed it to explore the conceptual clinical feasibility, particularly, in evaluating the relative significance of potential immune promotive/suppressive mechanisms induced by MSCs loaded with oncolytic viruses. We were able to delineate conditions which may significantly contribute to the success or failure of MSC-based virotherapy as well as generate new hypotheses. In fact, one of the most impactful outcomes shown by this investigation, not inferred from the experiments alone, was the initially counter-intuitive fact that using tumor-promoting MSCs as carriers is not only helpful but necessary in achieving tumor control. Considering the fact that it is still currently a controversial debate whether MSCs exert a pro- or anti-tumor action, mathematical models such as this one help to quantitatively predict the consequences of using MSCs for delivering virotherapeutic agents in vivo. Taken together, our results show that MSC-mediated systemic delivery of oncolytic viruses is a promising strategy for achieving synergistic anti-tumor efficacy with improved safety profiles.
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    Oncolytic potency and reduced virus tumorspecificity in oncolytic virotherapy. A mathematical modelling approach
    (Public Library of Science, 2017) Mahasa, Khaphetsi Joseph; Eladdadi, Amina; De Pillis, Lisette; Ouifki, Rachid
    In the present paper, we address by means of mathematical modeling the following main question: How can oncolytic virus infection of some normal cells in the vicinity of tumor cells enhance oncolytic virotherapy? We formulate a mathematical model describing the interactions between the oncolytic virus, the tumor cells, the normal cells, and the antitumoral and antiviral immune responses. The model consists of a system of delay differential equations with one (discrete) delay. We derive the model’s basic reproductive number within tumor and normal cell populations and use their ratio as a metric for virus tumor-specificity. Numerical simulations are performed for different values of the basic reproduction numbers and their ratios to investigate potential trade-offs between tumor reduction and normal cells losses. A fundamental feature unravelled by the model simulations is its great sensitivity to parameters that account for most variation in the early or late stages of oncolytic virotherapy. From a clinical point of view, our findings indicate that designing an oncolytic virus that is not 100% tumor-specific can increase virus particles, which in turn, can further infect tumor cells. Moreover, our findings indicate that when infected tissues can be regenerated, oncolytic viral infection of normal cells could improve cancer treatment.